HUP0004106A2 - Novel adenosine derivatives, process for producing them, medicaments containing the same as active agent and use of such compounds for producing pharmaceuticals - Google Patents

Abstract

The invention relates to new adenosine derivatives, pharmaceutical preparations containing them, as well as to a process suitable for the production of such derivatives and to the use of the new adenosine derivatives. In the general formula (I) of the adenosine derivatives according to the invention - R1 means - among other things - (C3-C7cycloalkyl)-(alk)n-group, aliphatic heterocyclic group with a 4-6 membered ring, straight or branched carbon chain, 1-12C alkyl group, condensed bicyclic an aromatic ring-containing group or a phenyl group; - R2 is an alkyl group with 1 to 3 carbon atoms, a halogen atom or a hydrogen atom; - R3 is a straight or branched fluorinated alkyl group of 1-6 carbon atoms. According to the invention, the compounds of the general formula (I) are prepared in such a way that the compound of the general formula (II) - R is a leaving group, P1 and P2 are a hydrogen atom or a suitable protecting group, and R1, R2 and R3 are defined in claim 1 - under basic conditions R1NH2 are reacted with a compound of the formula or its salt. The new compounds have plasma fat-lowering and heart-protective effects, as well as blood pressure-lowering effects. HE

Description

T ' / ... u/L/M ) '-X /«Λ c '^ ^r - ^U '

NEW ADENOSINE DERIVATIVES AND MEDICINAL PRODUCTS CONTAINING THESE PHARMACEUTICAL PRODUCTS

Application of the ΙíTÁffA ρ^ηνήΓΥή^τπ,τΙ , . J PUBLICATION COPY

The invention relates to novel adenosine derivatives, pharmaceutical compositions containing them, as well as to a process for preparing such derivatives and to the therapeutic use of novel adenosine derivatives.

The compounds of the invention which act as agonists at the adenosine A1 receptor have the general formula (I)

- R ² represents a C 1-3 alkyl group, a halogen atom or a hydrogen atom;

- R ³ represents a straight or branched fluorinated alkyl group having 1-6 carbon atoms;

- R ¹ is (1) a group of the general formula -(alk) _n -(C 3-7 cycloalkyl)- including bridged cycloalkyl groups - where alk is an alkylene group having 1-3 carbon atoms and n is 0 or 1 - which may optionally be substituted by one or more substituents, namely a hydroxyl group, a halogen atom and/or a C 1-3 alkoxy group;

(2) 4-6-membered, containing at least one heteroatom, namely an oxygen atom, a nitrogen atom and/or a sulfur atom, optionally with one or more substituents, namely a C1-3 alkyl group, a (C1-4 alkyl)-CO2- group, a (C1-3 a I ki I )-carbonyl i I- group, a (C1-3 alkyl)-(=O) _n -S- group, R ^b R ^a NCO

92188-5194-PT/tm

- an aliphatic heterocyclic group containing a group of general formula 2 - in which R ^a and R ^b independently represent a hydrogen atom or an alkyl group having 1-3 carbon atoms - and/or rings substituted with =O, with the proviso that if the heterocyclic ring contains a sulfur atom, this sulfur atom may optionally be substituted with ( = O) _n , in which n represents 1 or 2;

(3) a straight or branched carbon chain of 1-12 carbon atoms, optionally containing one or more oxygen atoms, a group of the general formula S(=O) _n - n is 0, 1 or 2 - or a nitrogen atom, optionally substituted with one or more phenyl groups, halogen atoms, hydroxyl groups and/or a group of the general formula NR ^a R ^b - both R ^a and R ^b are alkyl groups of 1-3 carbon atoms or hydrogen atoms - optionally substituted alkyl group;

(4) a fused bicyclic aromatic ring, in which B is a 5- or 6-membered heterocyclic aromatic group containing one or more oxygen, nitrogen or sulfur atoms; this bicyclic group is linked to the nitrogen atom of the general formula (I) through one of the ring atoms of ring A, and ring B is optionally substituted with a (C1-C3 alkyl) _-CO2 group;

(5) phenyl group optionally substituted with one or more substituents, namely halogen atom, HSO ₃ group, HO-(alk) _n group, cyano-(alk) _n group, (C 1-6 alkyl)-(0) _n group optionally substituted with one or more halogen atoms, nitro-(alk) n group, R ^o CO2-(alk) n -(O) m group, R°R ^d -CON-(alk) n -group, R ^c CO-(alk) _n -group, R ^e S0-

- with a 3 -(alk)n group, R ^e SO2-(alk)n group, R ^c R ^d SO2N-(alk)n group, R ^c O-(alk)n group, R ^e SO2NH-(CO)m-(alk)n group, R ^c CONH-(alk)n group and/or NR ^c R ^d -(alk) _n group, where m is 0 or 1;

n is 0 or 1;

alk represents a C1-6 alkylene group or a C2-6 alkenyl group;

(6) a phenyl group optionally substituted with a substituted 5- or 6-membered heterocyclic aromatic group, wherein said heterocyclic aromatic group is optionally substituted with a C1-3 alkyl group or a group of the general formula NR ^c R ^d ;

R ^c and R ^d are - independently of each other - a hydrogen atom or an alkyl group having 1-3 carbon atoms; or in the case of a group of the general formula NR°R ^d , R ^c and R ^d together with the nitrogen atom may form a 5- or 6-membered heterocyclic ring, which may optionally contain other heteroatoms and may optionally be substituted with one or more alkyl groups having 1-3 carbon atoms; and

R ^e is a C 1-3 alkyl group.

The invention also relates to the salts and solvates of the compounds of formula (I), in particular to the physiologically acceptable solvates and salts thereof.

The adenosine A1 agonists of the general formula (I) above advantageously exhibit greater activity at the adenosine A1 receptor than

- 4 on the other adenosine receptor types, especially the A3 receptor. In more detail, the compounds mentioned have little or no activity on the A3 receptor.

It should be noted that in the case where the R ¹ and/or R ² substituents in formula (I) contain one or more asymmetric carbon atoms, the invention covers all diastereoisomers of the compounds of formula (I) and all mixtures which can be formed from these diastereoisomers. The stereochemical configuration of the compounds of the invention is otherwise shown in the formula (I) given.

The term "alkyl" as used herein refers to a straight or branched chain alkyl group. For example, within the meaning of R ¹ and R ² , suitable alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, tert-butyl and 2,2-dimethylpropyl.

The term "alkylene group" as used herein refers to a straight or branched alkylene group having 1 to 6 carbon atoms, such as a methylene group.

The term "C2-6 alkenyl" as used herein refers to a straight or branched chain alkenyl group having from 2 to 6 carbon atoms. A suitable C2-6 alkenyl group is, for example, allyl.

The term "halogen atom" refers to a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

The term "aliphatic heterocyclic group" refers to a cyclic group of 4 to 6 carbon atoms in which one or more carbon atoms are replaced by nitrogen, oxygen and/or sulfur. This group may be optionally substituted as defined above.

The term "heterocyclic aromatic group" refers to an aromatic monocyclic or bicyclic ring system of 5 to 10 carbon atoms in which one or more carbon atoms are replaced by nitrogen, oxygen and/or sulfur. This group may be optionally substituted as defined above.

The pharmacologically acceptable salts of the compounds of formula (I) include salts with pharmacologically acceptable inorganic and organic acids. Examples of suitable acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, p-toluenesulfonic acid, tartaric acid, acetic acid, citric acid, methanesulfonic acid, formic acid, benzoic acid, malonic acid, naphthalene-2-sulfonic acid and benzenesulfonic acid. A particularly suitable pharmacologically acceptable salt of the compounds of formula (I) is the hydrochloride salt. Other acids which are not pharmacologically acceptable in themselves, such as oxalic acid, can be used as intermediates in the preparation of the compounds of the invention and their pharmacologically acceptable acid addition salts. Solvates can be, for example, hydrates.

R ³ is preferably a C 1-3 fluoroalkyl group, especially a fluoromethyl group. More preferably, the R ³ substituent is a trifluoromethyl group.

R ² is preferably hydrogen, methyl or halogen, more preferably hydrogen or chlorine.

R ¹ is preferably (alk) _n -(C 3-6 cycloalkyl) group, which

- in 6 n is 0 or 1, and the cycloalkyl group is unsubstituted or may be substituted by at least one substituent, namely a halogen atom - in particular a fluorine atom - and/or a hydroxyl group. Preferably n=0. More preferably, the cycloalkyl group is monosubstituted by a hydroxyl group or a fluorine atom, and the cycloalkyl ring has 5 carbon atoms. The R ¹ substituent may be an unsubstituted or substituted aliphatic heterocyclic group, the substituent of which may be a (C 1-4 alkyl)-CO2- group, a (C 1-3 alkyl)-carbonyl- group, a (C 1-3 alkyl)(=O)nS- group or a group of the general formula R ^a R ^b NCO- - where R ^a and R ^b have the meanings given above - and in the case where the ring contains an S heteroatom, this sulfur atom may optionally be substituted by (=O)n, if n is 0, 1 or 2. More preferably, the heterocyclic ring is unsubstituted or substituted by (C 1-4 alkyl)-CO2- groups, or in the case where the heteroatom is a sulfur atom, the (=O) _n substituent is attached to the sulfur atom in the heterocyclic ring. If the heteroatom in the ring is a sulfur atom, it is more preferred that this sulfur atom is unsubstituted.

The aliphatic heterocyclic group is preferably unsubstituted, or when substituted with a (C1-C4 alkyl)-CO ₂ group, the heteroatom is a nitrogen atom, and the substituent is directly attached to this nitrogen atom in the ring.

The heterocyclic ring is preferably 6-membered, and more preferably contains only one heteroatom - oxygen, nitrogen or sulfur.

The R ¹ substituent may also be present in the form of a straight or branched carbon chain, 1-5 carbon atom alkyl group, which in its chain - optionally - has at least one S(=O) _n group - in this .:. w.· ·τ

- In group 7, n is 0, 1 or 2 - and/or may be substituted by a nitrogen atom. In the case where there is an S(=O) _n group in the chain, n is preferably 1 or 2. The corresponding alkyl group is unsubstituted or substituted by at least one hydroxyl group.

R ¹ can also be a phenyl group substituted by one or more substituents, namely hydroxyl and/or halogen. The phenyl group is preferably 2,4-disubstituted. Preferably, both substituents are halogen, especially fluorine and chlorine. It is particularly preferred that one substituent is fluorine attached in the 2-position and the other is chlorine attached in the 4-position.

It is understood that the invention also applies to all combinations of the above-mentioned characteristic and preferred groups.

Typical compounds of the invention are as follows:

- N-(tetrahydropyran-4-yl)-5'-O-(trifluoromethyl)adenosine;

- N-(2-pyridin-4-ylethyl)-5'-0-(trifluoromethyl)-adenosine;

- N-[2S-fluoro-cyclopent-(S)-yl]-5'-O-(trifluoromethyl)-adenosine,

- N-(tetrahydrothiopyran-4-yl)-5'-O-(trifluoromethyl)-adenosine;

- N-(3,4-difluorophenyl)-5'-O-(trifluoromethyl)adenosine;

- N-(3-fluorophenyl)-5'-O-(trifluoromethyl)adenosine;

- N-(exo-bicyclo[2.2.1]hept-2-yl)-5'-O-(trifluoromethyl)-adenosine;

- N-(1,1-dioxo-hexahydro-1.delta.6-thiopyran-4-yl)-5'-0-(trifluoromethylj-adenosine;

- N-(tert-butyl)-5'-O-(trifluoromethyl)adenosine;

- 4-{9-[3R,4S-dihydroxy-5R-(trifluoromethoxymethyl)-tetrahydrofuran-2R-yl]-9H-purin-6-ylamino}-piperidin-1-carboxylic acid ethyl ester;

- N-(2S-hydroxycyclopent-(S)-yl)-5'-O-(trifluoromethyl)adenosine;

- N-(rel-2,3-dihydroxypropyl)-5'-O-(trifluoromethyl)adenosine;

- N-(tetrahydrofuran-3R-yl)-5'-O-(trifluoromethyl)-adenosine;

- N-(tetrahydrofuran-3S-yl)-5'-O-(trifluoromethyl)adenosine;

- N-{2-[9-[3R,4S-dihydroxy-5R-(trifluoromethoxymethyl)tetrahydrofuran-2R-yl]-9H-purin-6-ylamino]ethyl)acetamide;

- 5'-O-(trifluoromethyl)adenosine;

- 2-{9-[3R,4S-dihydroxy-5R-(trifluoromethoxymethyl)tetrahydrofuran-2R-yl]-9H-purin-6-ylamino}ethanesulfonic acid methylamide;

- 4-{9-[3R,4S-dihydroxy-5R-(trifluoromethoxymethyl)-tetrahydrofuran-2R-yl]-2-methyl-9H-purin-6-ylamino}-piperidine-1-carboxylic acid ethyl ester,

- 2-methyl-N-(tetrahydro-pyran-4-yl)-5'-O-(trifluoromethyl)-adenosine;

- 5'-O-(3-fluoropropyl)-N-(tetrahydropyran-4-yl)-adenosine;

- 2-chloro-5'-O-(3-fluoropropyl)-N-(tetrahydropyran-4-yl)adenosine;

- N-cyclopentyl-5'-O-(2,2,2-trifluoroethyl)-adenosine;

- N-(tetrahydropyran-4-yl)-5'-O-(2,2,2-trifluoroethyl)-adenosine;

- N-(2R-hydroxycyclopent-(R)-yl)-5'-O-(2,2,2-trifluoroethyl)adenosine; and

- N-(4-fluorophenyl)-5'-O-(2,2,2-trifluoroethyl)adenosine.

The compounds of the invention can also be used as lipolytic agents, i.e. they reduce the concentration of free fatty acids in the plasma. The increased fat content in the blood of patients treated with these compounds can therefore be reduced. The compounds of the invention are also able to reduce high blood glucose, insulin and ketone body concentrations, and therefore may be useful in the treatment of diabetic patients. Given that substances that act against lipolysis reduce the increased fat content and fibrinogen activity of the blood, the compounds of the invention may also have antiatherosclerotic activity. The antilipolytic activity of the compounds of the invention has already been demonstrated on the basis of their ability to reduce the concentration of non-esterified fatty acids (NEFA)

- 9 in fasted rats administered such compounds as described by P. Strong et al. [Clinical Science, 84, 663-669 (1993)].

In addition to their antilipolytic effects, the compounds of the invention are able to independently influence cardiac function by reducing heart rate and conduction. These compounds can therefore be used for the treatment of a number of cardiovascular disorders, such as irregular heart rhythms, especially after myocardial infarction and coronary artery spasm.

In addition, the compounds of the invention can be used as cardioprotective agents, in view of their suitability for the treatment of heart diseases causing local anaemia. "Heart diseases causing local anaemia" include disorders causing damage to the myocardium due to both local anaemia and reperfusion, such as those associated with coronary artery bypass grafting (CABG), percutaneous transluminal coronary angioplasty (PTCA), blunt cardiac injury, acute myocardial infarction, thrombolysis, stable and unstable angina, and cardiac surgery, including in particular heart transplantation. The compounds of the invention can also be used for the treatment of damage to other organs due to local anaemia. The compounds of the invention may also be useful in the treatment of other disorders resulting from widespread atheromatous diseases, such as peripheral vascular disease (PVD) and stroke.

The compounds of the invention may also inhibit renin release and may therefore be useful in the treatment of both hypertension and heart failure. The compounds may therefore also be used as CNS agents, for example as hypnotics, sedatives, analgesics and/or anticonvulsants, particularly in the treatment of patients with epilepsy.

The compounds of the invention can also be used for the treatment of sleep apnea.

The compounds of formula (I) and their pharmacologically acceptable acid addition salts can be used as analgesics, i.e. they can be used to treat or prevent pain. They can be used to improve the condition of patients, usually humans, suffering from pain, to alleviate the pain of patients. The compounds of formula (I) and their pharmacologically acceptable acid addition salts can therefore be used as prophylactic analgesics for acute pain, such as musculoskeletal pain, post-operative pain and pain associated with surgical interventions, as well as chronic pain, such as pain associated with chronic inflammation, such as rheumatoid arthritis and osteoarthritis, as well as neuropathic pain (such as post-herpetic neuralgia, diabetic neuralgia, trigeminal neuralgia, pain associated with functional bowel disorders, such as irritable bowel syndrome, non-cardiac chest pain and pain sustained by the sympathetic nervous system), as well as pain associated with cancer and fibromyalgia. The compounds of formula (I) can be used to treat and prevent pain associated with migraine, hypertensive headache, cluster headache and functional bowel disorders (e.g. IBS), as well as non-cardiac chest pain and non-ulcer indigestion*· · »·«*<··* ·*/*

- 11 for the sake of.

The invention therefore provides compounds of formula (I) and their physiologically acceptable salts and solvates for medical use, in particular for the treatment of humans or animals who are in a condition where a reduction in plasma free fatty acid content or heart rate and conduction is beneficial, or where the treatment includes the treatment of heart disease with local anaemia, peripheral vascular disease or stroke, or who are suffering from a central nervous system (CNS) disorder, sleep apnea or pain.

The invention also provides a method for treating humans or animals who are in a condition that would benefit from a reduction in plasma free fatty acid content or heart rate and conduction, or who are suffering from or are susceptible to heart disease with focal anemia, peripheral vascular disease or cerebral vasospasm, or who are suffering from a central nervous system (CNS) disorder, sleep apnea or pain. The method comprises administering to the patient an effective amount of a compound of formula (I) or a pharmacologically acceptable salt or solvate thereof.

In connection with the above-mentioned treatment of local anemia, we mention that, according to our experience, one of the particularly unexpected features of the invention is that the compounds of general formula (I) not only provide protection against myocardial infarction when administered before the development of the anemia state, but also in that case ’··* * .·. **í‘

- 12 also when administered after the event that caused the anemia, before reperfusion. This means that the method according to the invention can be used not only in the case of a planned or expected anemia state - for example, cardiac surgery - but also in the case of a sudden and unexpected anemia state - for example, heart attack and unstable coronary spasm.

It is noted that "treatment" as used herein may be acute treatment or preventive treatment as well as treatment aimed at alleviating an already established symptom complex.

In addition to those mentioned, the invention also relates to pharmaceutical compositions which, in addition to a carrier and/or binder used for the preparation of pharmaceuticals, contain at least one of the compounds of general formula (I) and their pharmacologically acceptable salts or solvates.

On the other hand, the invention provides pharmaceutical compositions for the preparation of pharmaceuticals, which contain at least one compound of the general formula (I) or a pharmacologically acceptable salt or solvate thereof as an active ingredient in addition to a carrier and/or binder, and which are suitable for medical treatment, in particular for treating humans or animals who are in a condition that benefits from a reduction in plasma free fatty acid content or heart rate and conduction, or who suffer from or are susceptible to heart disease with local anemia, peripheral vascular disease, stroke, central nervous system (CNS) disorder, sleep apnea or pain.

The invention also relates to a process for the preparation of pharmaceutical compositions, which comprises at least one (I) compound.

- 13 ’·-* ί ν*. “*· a compound of the formula or a pharmacologically acceptable salt or solvate thereof is mixed with a pharmacologically acceptable carrier and/or excipient.

The compositions of the invention can be formulated into preparations suitable for topical, oral, buccal, parenteral or rectal administration, as well as into medicaments suitable for inhalation or insufflation. The compositions of the invention are preferably administered orally. The compositions can also be adapted for the preparation of sustained-release preparations.

For topical applications, it is advisable to present pharmaceutical products in the form of a transdermal patch.

Tablets and capsules for oral administration may contain conventional excipients such as binders, such as starch, mucilage or poly(vinylpyrrolidone), fillers, such as lactose, microcrystalline cellulose or corn starch, lubricants, such as magnesium stearate or stearic acid, disintegrating agents, such as potato starch, croscarmellose sodium or sodium glycolate derived from starch, and/or wetting agents, such as sodium lauryl sulfate. The tablets may be coated using methods well known in the art. Liquid oral preparations, such as aqueous or oily suspensions, solutions, emulsions, syrups and elixirs, may be prepared, as well as anhydrous preparations which may be reconstituted with water or other suitable vehicle before use. These liquid preparations may contain conventional additives, for example suspending agents such as sorbitol syrup, methylcellulose or carboxymethylcellulose, emulsifying agents such as sorbitan monooleate, optionally with

- 14 non-aqueous vehicles including essential oils, such as propylene glycol or ethyl alcohol, and preservatives, such as methyl p-hydroxybenzoate, propyl p-hydroxybenzoate or sorbic acid. The compositions may optionally also contain buffer salts, flavorings, colorings and sweeteners, such as mannitol.

For buccal administration, the compositions may be formulated in the form of conventionally formed tablets or lozenges.

The compounds of formula (I) may be formulated for parenteral administration by bolus injection or continuous infusion. These preparations may be presented in unit dose form in ampoules or in multidose containers, with the addition of a preservative. The compositions may be suspensions, solutions or emulsions in oily or aqueous vehicles and may contain formulation aids such as suspending agents, stabilizing agents and/or dispersing agents. Alternatively, the active ingredient may be presented in powder form for reconstitution with a suitable vehicle, such as sterile water free from pyrogens, before use.

Suppositories can also be formulated from the compounds of general formula (I), which contain, for example, raw materials traditionally used for the production of suppositories, such as cocoa butter or other glycerides.

The recommended daily dose of the compounds of the invention is 1 mg to 2 g, preferably 1 mg to 100 mg, per unit dose for a human weighing approximately 70 kg. This amount of active ingredient can be administered, for example, 1 to 4 times a day. It should be noted in this connection that routine changes in dosage may be necessary depending on the age and condition of the patient. The dosage also depends on the route of administration.

The invention also provides the use of the compounds of formula (I) or their pharmacologically acceptable salts or solvates for the preparation of pharmaceutical compositions for the treatment of humans and animals who are in a condition that would benefit from a reduction in plasma free fatty acid content or heart rate and conduction, or who suffer from or are predisposed to heart disease with focal anemia, peripheral vascular disease or stroke, or who suffer from a central nervous system (CNS) disorder, sleep apnea or pain.

The compounds of formula (I) and their physiologically acceptable salts or solvates can be prepared by the processes described below, which are also subject of the invention. In the following description, the meanings of the substituents R ¹ , R ² and R ³ are those given in the interpretation of formula (I), unless otherwise indicated.

According to the first general process - (A) - compounds of general formula (I) are prepared by reacting compounds of general formula (II) with R ¹ NH ₂ or its salt in a basic medium.

- L is a leaving atom or leaving group, for example a chlorine atom; and 1 2

- P and P represent a hydrogen atom or a protecting group, for example an acetyl group.

In order to prepare the compounds of general formula (I), the compounds of general formula (II) and the compounds of general formula R ¹ NH ₂ are reacted directly in the presence or absence of a solvent, for example an alcohol (such as a lower alkanol, for example isopropanol, tert-butanol or 3-pentanol), an ether (such as tetrahydrofuran or dioxane), a substituted amide (such as dimethylformamide), a halogenated hydrocarbon (such as chloroform) or acetonitrile, and preferably at elevated temperatures (for example between ambient temperature and the reflux temperature of the solvent) in the presence of a suitable acid scavenger, for example an inorganic base (such as sodium carbonate or potassium carbonate) or an organic base (for example triethylamine, diisopropylethylamine or pyridine).

This reaction may be preceded or followed by in situ removal of the protecting groups P ¹ and P ² if desired. For example, if P ¹ and P ² are acetyl groups, removal may be carried out at a suitable temperature in a solvent, such as methanol, with an amine, such as ammonia or tert-butylamine.

Compounds of general formula (II) can be prepared by reacting compounds of general formula (III) - in general formula (III) P ³ is a suitable protecting group, for example a C 1-3 alkyl group or an acetyl group, and P ¹ , P ² and R ³ are as defined above - and compounds of general formula (IV) - in general formula (IV) L and R ² are as defined above -.

The reaction is preferably carried out in a suitable solvent, for example acetonitrile, in the presence of a silylating agent, for example trimethylsilyl trifluoromethanesulfonate, and a base, for example diazabicyclo[5.4.0]undec-7-ene (DBU). Alternatively, the compound of formula (IV) is first silylated with a suitable silylating agent, for example hexamethyldisilazane, and the silylated intermediate is then reacted with a compound of formula (III) and a suitable Lewis acid, for example trimethylsilyl trifluoromethanesulfonate, in a suitable solvent, for example acetonitrile.

Compounds of general formula (IV) are known to those skilled in the art.

- 17 are known or can be prepared in a manner similar to the processes used for the preparation of known compounds of general formula (IV).

Compounds of formula (III) can be prepared from alternatively protected compounds by replacing the variable protecting groups P ¹ and P ² with substituents. Thus, for example, in the case where P ¹ and P ² are acetyl groups, compounds of formula (III) can be prepared by acid-catalyzed removal of the alkylidene protecting group of compounds of formula (V) - in formula (V) P ⁴ and P ⁵ are C 1-3 alkyl groups and P ³ is as defined above - followed by in situ acylation, for example in a solvent such as dichloromethane - with acetic anhydride in the presence of a base such as pyridine.

Compounds of formula (V) are known or can be prepared in a manner similar to that used in the art for the preparation of known compounds of formula (V). For example, compounds of formula (V) containing methyl groups at P ³ , P ⁴ and P ⁵ and trifluoromethyl at R ³ can be prepared from known compounds of formula (VI) by reacting said compounds with a suitable base, for example sodium hydride, followed by reaction with carbon disulfide in combination with an alkylating agent of formula R ⁴ L ^, for example methyl iodide (wherein L is a leaving atom or group, for example halogen, such as bromine or iodine, and R ⁴ is an alkyl group as defined above), to produce compounds of formula (VII).

Compounds of formula (VII) can be treated with a suitable brominating agent - for example dibromomethylhydantoin and the method of Hyoma T. et al. - to produce compounds of formula (V).

- according to the method described by 18 colleagues [Tetrahedron Letters 1992, 41734176] in a suitable solvent with pyridine/hydrogen fluoride complex.

Compounds of formula (V) can also be prepared by treating known compounds of formula (VIII) with tris-(dimethylamino)sulfur trifluoromethoxide in a suitable solvent, for example dichloromethane.

It will be understood by those skilled in the art that the acetyl group in any compound may be replaced by a suitable protecting group, for example, another ester group.

Compounds of formula (I) or (II) can also be prepared by analogous methods from compounds in which the alkylidene groups defined by the substituents P ⁴ and P ⁵ are replaced by groups P ¹ and P ^2. Substitution reactions resulting in the exchange of one protecting group for another are well known to those skilled in the art.

According to a further process variant - B) - the compounds of general formula (I) are converted into other compounds of general formula (I) by modifying the R ¹ , R ² or R ³ substituents therein.

Compounds of general formula (II) can also be advantageously prepared by removing the alkylidene protecting group from compounds of general formula (IX) - in general formula (IX) P ⁴ , P ⁵ , R ³ , R ² and L are as defined above.

Compounds of formula (IX) can be prepared by treating compounds of formula (X) in which P ⁴ and P ⁵ are as defined above with a halogenating agent (e.g. chlorinating agent) under conventional conditions. For example, the chlorination can be advantageously carried out by treating compounds of formula (X) with an organic base, e.g. 4-dimethylaminopyridine.

- 19 - in the presence of phosphorus oxychloride in a suitable solvent, for example acetonitrile, at an elevated temperature, for example between ambient temperature and the reflux temperature of the solvent.

Compounds of formula (X) can be prepared by reacting compounds of formula (XI) in a suitable solvent, such as ethanol, in the presence of a suitable catalyst, such as palladium or carbon, with hydrogen or a hydrogen source, such as ammonium formate.

Compounds of formula (XI) can be prepared by reacting compounds of formula (XII) with an alcohol of formula R ³ OH in a suitable inert solvent, for example dimethylformamide, in the presence of a strong base, for example sodium hydride.

Compounds of formula (XII) can be prepared by reacting compounds of formula (XIII) with benzyl alcohol in an inert solvent, such as tetrahydrofuran, in the presence of a suitable strong base, such as sodium hydride.

Compounds of formula (XIII) may be prepared by treating compounds of formula (XIV) with methanesulfonyl chloride in a suitable solvent, for example dichloromethane, in the presence of a suitable base, for example triethylamine, diisopropylethylamine or pyridine.

It should be noted that although in connection with process variant B) described above, the interconversion of substituents is described only as the final step of the process, R ¹ or R ² or R ³ can be converted to a different R ¹ or R ² or R ³ group by an intermediate step throughout the synthesis.

Compounds of formula (XIV) are known in the art or can be prepared from known compounds using methods similar to those used in the art for the preparation of known compounds of formula (XIV).

Certain compounds of general formulae (II), (III) and (V) are novel intermediates which also form the subject of the invention.

Compounds of the general formula R ¹ NH2 are known or, with a few exceptions noted in the experimental section below, can be prepared from known compounds by conventional methods.

According to a further process variant - C) - compounds of general formula (I) can also be prepared from compounds in which in general formula (XV) P ¹ and P ² represent the appropriate protecting group already defined above and P ⁶ also represents an appropriate protecting group. Thus, for example, in the case where R ² represents a chlorine atom, preferably each of the substituents P ¹ , P ² and P ⁶ is a benzoyl group (the compound thus defined is known).

Compounds of general formula (I) can also be prepared by reacting compounds of general formula (XV) with compounds of general formula R 1 NH 2 in the absence of a solvent or in the presence of a solvent, such as an alcohol (such as a lower alkanol, such as isopropanol, t-butanol or 3-pentanol), an ether (such as tetrahydrofuran or dioxane), a substituted amide (such as dimethylformamide), a halogenated hydrocarbon (such as chloroform) or acetonitrile, at a higher temperature, such as between ambient temperature and the reflux temperature of _the solvent, in the presence of a suitable acid scavenger, such as an inorganic base (such as sodium carbonate or potassium carbonate) or an organic base (such as ^{triethylamine} , diisopropylethylamine or pyridine).

This reaction may be preceded or followed by in situ removal of the protecting groups P ¹ , P ² and P ⁶ , if desired. For example, if P ¹ , P ² and P ⁶ represent benzoyl groups, these groups may be removed in a solvent, such as methanol, with a carbonate, such as potassium carbonate, to give compounds of formula (XVI).

When compounds of general formula (XVI) are reacted with the protecting groups P ⁴ and P ⁵ as defined above, compounds of general formula (XVII) can be formed.

The R ³ group can then be introduced into the molecule using methods readily available to those skilled in the art, and the compound can then be deprotected as described in Method A) discussed above.

Specific optical isomers of the compounds of formula (I) may be prepared using conventional methods, for example by synthesis from a suitable asymmetric starting material according to any of the methods described herein or, where appropriate, by separation of a mixture containing isomers of the compounds of formula (I) by conventional means, for example by fractional crystallization or chromatography.

By using the general process variants described above, the compounds of formula (I) are obtained in the form of a salt, preferably a pharmacologically acceptable salt. If desired, these salts can be converted into the corresponding free bases using conventional methods.

Pharmacologically acceptable acid addition salts of the compounds of formula (I) may be prepared by reacting the compounds of formula (I) with a suitable acid in the presence of a suitable solvent, for example acetonitrile, acetone, chloroform, ethyl acetate or an alcohol, for example methanol, ethanol or isopropanol. Pharmacologically acceptable base addition salts may be prepared in a similar manner by treating the compounds of formula (I) with a suitable base. Pharmacologically acceptable salts may also be prepared from other salts, including other pharmacologically acceptable salts, by conventional methods.

The invention is further illustrated, without any limitation, by the following intermediates and examples.

Standard conditions for high performance liquid chromatography operations were used as follows.

Typically used automated preparative high-performance liquid chromatography column, chromatography conditions and eluent used for chromatography

The automated preparative high-performance liquid chromatography (autoprep. HPLC) operations were performed on a 100 mm high, 22 mm internal diameter Supelco ABZ+ 5pm column. A solvent mixture consisting of i) 0.1% aqueous formic acid solution and ii) 0.05% acetonitrile formic acid solution was used as eluent. The composition of the eluent, which was flowed at a volumetric rate of 4 ml per minute, is given as the percentage of component ii). Unless otherwise indicated, the concentration of component ii) in the eluent was increased from 0% to 95% over 20 minutes.

LC/MS method

In this method, a 3.3 cm high, 4.6 mm internal diameter ABZ+PLUS column was used. The following solvents were used as eluents: A) an aqueous solution containing 0.1 vol.% formic acid and 0.077 mixed % ammonium acetate and B) a mixture of acetonitrile and water in a ratio of 95:5 vol.% supplemented with 0.05 vol.% formic acid. The volume flow rate of the solvents was 1 ml/min. The following concentration gradient was used:

• ·· · ····· • · · ·· · Μ · *

100% component A) for 0.7 minutes; a mixture of components A) and B), in which the concentration of component B) changes from 0% to 100% in 3.5 minutes; maintaining the concentration of component B) at 100% for 3.5 minutes, then restoring the concentration of component A) to 100% in 0.3 minutes. The method used a “platform” spectrometer suitable for micromass analysis in electrospray ionization mode, with positive ion/negative ion switching, in the range of 80-1000 atomic mass units.

High-performance liquid chromatography method

According to the high-performance liquid chromatography analytical method, a 150 mm high, 4.6 mm internal diameter inertsil ODS2 column was used. For the elution

A) 0.1% by volume phosphoric acid; and

B) A mixture of 95:5 volume percent acetonitrile and water containing 0.1 vol.% phosphoric acid was used at a volume flow rate of 1.0 ml/min.

Regarding the concentration gradient, the following protocol was used: 100% component A) for 2 minutes; use of mixtures of components A) and B) in which the concentration of component B) changes from 0% to 100% over 40 minutes; keeping the concentration of component B) at 100% for 10 minutes.

Flash chromatography was performed on Merck silica gel (Merck 9385) or Merck alumina (Merck 1077).

1. intermediate

Dithiocarboxylic acid-10-(6R-methoxy-2,2-dimethyltetrahydro(3aR,6aR)furof3,4-b][1,31dioxol-4R-yl-methyl-ester-(S-methyl)-ester • · »····· ·-.· : .:. w.· ··:·

- 24 5.20 g of [6R-methoxy-2,2-dimethyl-tetrahydro-(3aR,6aR)furo[3,4d][1,3]dioxol-4R-yl]-methanol were dissolved in 70 ml of anhydrous tetrahydrofuran, then the resulting solution was treated with 1.20 g of a 60% oily sodium hydride suspension added in portions over 10 minutes at 22 °C under nitrogen. After 20 minutes, 5 ml (6.33 g) of carbon disulfide were added, and the resulting mixture was stirred at 22 °C for a further 20 minutes. Then 2 ml of iodomethane were added, and the resulting mixture was kept at 22 °C for a further 0.5 hour, then the solvent was removed in vacuo. The residue was treated with 80 ml of water and extracted with ethyl acetate. The combined ethyl acetate extracts were dried over sodium sulfate and concentrated in vacuo to give 8.60 g of the product as a pale yellow oil.

TLC SiO ₂ (cyclohexane ether = 1:1) Rf = 0.62.

Intermediate 2 (3aR,4R,6aR)-4-Methoxy-2,2-dimethyl-6-(trifluoromethoxymethyl)-tetrahydrofuro[3,4-difluoro]-1,3]dioxole 4.29 g of 1,3-dibromo-5,5-dimethylhydrazine were suspended in 10 ml of dichloromethane. 10 ml (approximately 80 equivalents) of hydrogen fluoride-pyridine complex were added to the suspension. The mixture was cooled to -70 °C under nitrogen, then 1.472 g of dithiocarboxylic acid [O-(6R-methoxy-2,2-dimethyl-tetrahydro(3aR,6aR)furo[3,4-d][1,3]dioxol-4R-yl-methyl]-ester-(S-methyl)-ester dissolved in 10 ml of dichloromethane was added. The mixture was then stirred at a temperature between 0 °C and 5 °C, and then the reaction was quenched by the slow addition of 250 ml of 2 M sodium carbonate solution containing 10 g of sodium metabisulfite to the mixture. Subsequently, 60 ml of dichloromethane were added, and the aqueous phase was further extracted with 100 ml of • · ······· ·..· : ./. „.· ·τ

- 25 was extracted with dichloromethane. The combined dichloromethane extracts were washed with 5% sodium metabisulfite solution and 2 M sodium carbonate solution, dried over sodium sulfate and evaporated in vacuo. The residue was purified by flash chromatography on 150 g silica gel. Mixtures of cyclohexane and diethyl ether (4:1-2:1) were used as eluents. In this way, 650 mg of the title compound was obtained as a pure, oily substance.

TLC S1O2 (cyclohexane-ether = 1:1) Rf = 0.5.

Intermediate 2 (alternative method) 1 g of trifluoromethanesulfonic acid 6R-methoxy-2,2-dimethyl-tetrahydro(3aR,6aR)furo[3,4-d][1,3]dioxo I-4R-yl-methyl ester was dissolved in 1 ml of dichloromethane, then the resulting solution was treated with 1.12 g of tris(dimethylamino)sulfonium trifluoromethoxide, and the resulting mixture was stirred under nitrogen at 22 °C for 26 hours. The solution was evaporated in vacuo, and the evaporation residue was purified by flash chromatography on silica gel (25 g). A 4:1 mixture of cyclohexane and diethyl ether was used as the eluent. In this way, 237 mg of the title compound was obtained as a clear, oily substance.

3. intermediate

Acetic acid-(2R,4R-diacetoxy-5R-(trifluoromethoxymethyl)-tetrahydrofuran-3R-yl ester (anomer a) and

Acetic acid-(2S,4R-diacetoxy-5R-(trifluoromethoxymethyl)-tetrahydrofuran-3R-yl]-ester (6 anomer) 0.61 g of (3aR,4R,6R,6aR)-4-methoxy-2,2-dimethyl-6-(trifluoromethoxy)-methyl-tetrahydrofuro[3,4-d][1,3]dioxole was dissolved in 1 ml of a mixture of trifluoroacetic acid and water in a ratio of 9:1.

- 26 then the resulting solution was left to stand at 22 °C for one hour. The solvent was removed in vacuo and the residue was co-evaporated with toluene. The evaporation residue was dissolved in a mixture of 15 ml of dichloromethane and 5 ml of pyridine, then 5 mg of 4-dimethylaminopyridine and 3 ml of acetic anhydride were added. The solution was left to stand at 22 °C for 17 hours and then evaporated in vacuo. The evaporation residue was dissolved in 150 ml of ethyl acetate, the solution was washed with 2 M hydrochloric acid solution and 8% aqueous sodium bicarbonate solution, dried over sodium sulfate and evaporated in vacuo. Flash chromatography was carried out on 30 g of silica. Mixtures of cyclohexane and diethyl ether (3:1-1:1) by volume were used as eluents. First, 237 mg of acetic acid [2S,4R-diacetoxy-5R-(trifluoromethoxymethyl)-tetrahydrofuran-3R-yl]-ester (β-anomer) were obtained, then 202 mg of acetic acid [2R,4R-diacetoxy-5R-(trifluoromethoxymethyl)-tetrahydrofuran-3R-yl]-ester (α-anomer) were obtained.

(β-anomer): mass spectrum: m/z 362 (MNH ₄ ⁺ ). (α-anomer: mass spectrum: m/z 362 (MNH ₄ ⁺ ).

4. intermediate

Acetic acid [4R-acetoxy-5R-methoxy-2R-(trifluoromethoxymethyl)tetrahydrofuran-3R-yl] ester

6.67 g of (3aR,4R,6R,6aR)-4-methoxy-2,2-dimethyl-6-(trifluoromethoxymethyl)-tetrahydrofuro[3,4-d][1,3]dioxole were dissolved in 100 ml of methanol. The resulting solution was treated with 3.0 ml of concentrated hydrochloric acid and the mixture was refluxed for 65 hours. After 24 and 48 hours, 20 ml of methanol were distilled off and fresh methanol was added to the reaction mixture. The solvent was evaporated from the solution in vacuo and the residue was co-evaporated with 10 ml of pyridine. The evaporation residue was dissolved in 150 ml of dichloromethane and 15

- in a mixture of 27 ml of pyridine. About 20 mg of 4-(dimethylamino)pyridine and 9 ml of acetic anhydride were added and the solution was left to stand at 22 °C for 24 hours. The solvents were evaporated in vacuo and the residue was treated with 150 ml of 8% sodium bicarbonate solution and extracted with 2x150 ml of ethyl acetate. The organic extracts were dried with sodium sulfate and evaporated in vacuo. The evaporation residue was purified by flash chromatography on 300 g of silica. Elution was carried out with mixtures of cyclohexane and diethyl ether (2:1-1:1) in a volume ratio. In this way, 2.45 g of the title compound was obtained as a colorless, oily substance.

TLC _SiO2 (ether) Rf = 0.72.

5. intermediate

Acetic acid [4R-acetoxy-2R-(6-chloropurin-9-yl)-5R-(trifluoromethoxymethyl)tetrahydrofuran-3R-yl] ester

A mixture of 0.770 g of 6-chloropurine, 4 ml (18.96 mmol) of 1,1,1,3,3,3-hexamethyldisilazane and 10 ml of toluene was refluxed under nitrogen for 3 hours. The solvent was removed in vacuo and the residue was co-evaporated with 10 ml of toluene. The evaporation residue was taken up in 12 ml of anhydrous acetonitrile. The resulting mixture was treated with 425 mg of acetic acid [2S,4R-diacetoxy-5R-(trifluoromethoxymethyl)-tetrahydrofuran-3R-yl]-ester, 0.28 ml of 1,8-diazabicycloundec-7-ene and 0.41 ml of trimethylsilyl trifluoromethanesulfonate. The resulting mixture was stirred at 22 °C under nitrogen for 20 h and then refluxed for 2 h. The resulting orange solution was cooled to 20 °C, poured into 100 ml of 8% sodium bicarbonate solution and extracted with ethyl acetate. The organic extracts were dried over sodium sulfate, concentrated in vacuo • · «·€>·*>

‘'· · ♦ V M > * ·

- 28 was evaporated and the evaporation residue was purified by flash chromatography on 60 g of silica. Mixtures of cyclohexane and diethyl ether (1:1-1:4) were used as eluents. In this way, 345 mg of the title compound was obtained.

TLC _SiO2 ( _Et2O ) Rf = 0.6.

5, intermediate (alternative method)

A mixture of 0.31 g of 6-chloropurine, 2 ml of 1,1,1,3,3,3-hexamethyldisilazane and 6 ml of toluene was refluxed under nitrogen for 2 hours. The solvent was evaporated in vacuo and the residue was co-evaporated with anhydrous toluene. The solid residue was dissolved in 12 ml of anhydrous acetonitrile and 0.29 g of acetic acid [4R-acetoxy-5R-methoxy-2R-(trifluoromethoxymethyl)-tetrahydrofuran-3R-yl] ester, 0.24 ml of 1,8-diazabicycloundec-7-ene and 0.35 ml of trimethylsilyl trifluoromethanesulfonate were added. The resulting solution was refluxed under nitrogen for 2 hours, then cooled and left to stand at 22 °C for 17 hours. Then 0.35 ml of trimethylsilyl trifluoromethanesulfonate was added and the solution was refluxed under nitrogen for a further 5 hours. Then 30 ml of 8% sodium bicarbonate solution was added to the solution and the resulting mixture was extracted with dichloromethane. The organic extracts were dried with sodium sulfate and evaporated in vacuo. The dark, oily material thus obtained was purified by flash chromatography on 25 g of silica. Mixtures of cyclohexane and diethyl ether (1:1-1:4) by volume were used as eluents. In this way, 304 mg of the title compound was obtained.

Mass spectrum: m/z = 439/441 (MH ⁺ ).

' »* * M. · ··*·

Intermediate 6 (2R,3R,4S,5R)-2-(6-Chloro-purin-9-yl)-5-(trifluoromethoxymethyl)-tetrahydrofuran-3,4-diol 345 mg of acetic acid [4R-acetoxy-2R(6-chloro-purin-9-yl)-5R-(trifluoromethoxymethyl)-tetrahydrofuran-3R-yl] ester was dissolved in 1 ml of methanol, the solution was cooled to a temperature between 0 °C and 5 °C, then 0.25 ml of tert-butylamine was added. The resulting solution was left to stand at a temperature between 0 °C and 5 °C for one hour, then evaporated to dryness in vacuo. In this way, 265 mg of the title compound was obtained in the form of a colorless, foam-like substance.

TLC SiO ₂ (CH ₂ Cl ₂ :MeOH = 9:1) Rf = 0.31.

7. intermediate

Acetic acid [4R-acetoxy-2R-(6-chloro-2-methyl-purin-9-yl)-5R-(trifluoromethoxymethyl)-tetrahydrofuran-3R-yl]-ester

A mixture of 0.734 g of 6-chloro-2-methylpurine hydrochloride, 7 ml of 1,1,1,3,3,3-hexamethyldisilazide and 20 ml of anhydrous toluene was refluxed under nitrogen for 1.5 hours. The solvent was evaporated from the mixture in vacuo and the residue was co-evaporated with toluene. The evaporation residue was dissolved in 15 ml of anhydrous acetonitrile. To the solution was added 0.566 g of acetic acid [4R-acetoxy-5R-methoxy-2R-(trifluoromethoxymethyl)-tetrahydrofuran-3R-yl] ester, 0.48 ml of 1,8-diazabicycloundec-7-ene and 1.03 ml of trimethylsilyl trifluoromethanesulfonate, the resulting mixture was stirred at 22 °C for 10 minutes and then refluxed under nitrogen for two hours. After adding a further amount of trifluoromethanesulfonate (0.7 ml), the solution was refluxed under nitrogen for a further 1.5 hours. To the dark mixture was added 100 ml of 8% aqueous sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethyl acetate. The organic extracts were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on 60 g of silica using diethyl ether as eluent. 290 mg of product was obtained.

TLC _SiO2 ( _Et2O ) Rf =0.17.

8. intermediate

2-(2S-Hydroxy-(S)-cyclopentyl)-isoindole-1,3-dione

1.20 g of (1 S,2S)-2-aminocyclopentanol hydrochloride was dissolved in a solution containing 497 mg of sodium methoxide and 10 ml of methanol. The resulting solution was filtered and evaporated in vacuo. The evaporation residue was dissolved in 30 ml of toluene, 1.55 g of phthalic anhydride was added to the solution, and the resulting mixture was refluxed for 24 hours. After cooling, ethyl acetate was added and the resulting mixture was filtered. The filtrate was evaporated in vacuo, and the evaporation residue was purified by flash chromatography on 40 g of silica. A 2:1 mixture of cyclohexane and ethyl acetate was used as eluent. In this way, 1.08 g of the title compound was obtained as a colorless solid.

Mass spectrum: m/z 232 (MH ⁺ ).

9. intermediate

2-(2S-Fluoro-(S)-cyclopentyl)-isoindole-1,3-dione

3.42 g of 2-(2S-hydroxy-(S)-cyclopentyl)-isoindole-1,3-dione were dissolved in 55 ml of anhydrous dichloromethane, and 3.43 ml of diethylaminosulfur trifluoride were added to the solution. The resulting solution was refluxed under nitrogen for 72 hours. The solution was then carefully poured into 100 ml of 8% sodium bicarbonate solution and the organic phase was separated. The aqueous phase was extracted with additional dichloromethane. The organic phases were combined, dried over magnesium sulfate and evaporated in vacuo. The evaporation residue was purified by flash chromatography on 100 g of silica. Elution was carried out with a 1:1 mixture of cyclohexane and ethyl acetate to give 1.25 g of the title compound as a cream-colored powder.

Mass spectrum: m/z 234 (MH ⁺ ), 251 (MNH ₄ ⁺ ).

Intermediate 10 (1S,2S)-2-Fluorocyclopentylamine hydrochloride

A mixture of 6.75 g of 2-(2S-fluoro-(S)-cyclopentyl)-isoindole-1,3-dione, 1.55 ml of hydrazine hydrate and 200 ml of ethanol was treated with 1.55 ml of water and the resulting mixture was refluxed for 4 hours. The mixture was then cooled to 20 °C and filtered. Concentrated hydrochloric acid was added to the filtrate until a pH of 1 was reached. The solution was evaporated in vacuo and the evaporation residue was taken up in water. The resulting mixture was filtered and the filtrate was evaporated in vacuo. The evaporation residue was recrystallized from a 3:1 mixture of ethyl acetate and methanol by volume after hot filtration. In this way, 2.59 g of the title compound was obtained as an off-white solid.

NMR δ (DMSO): 8.3 (3H, broad s, -NH ₃ ⁺ ), 5.04 (1H, dm, CHF, J FCH, 52 Hz), 3.49 (1H, broad dm, CH, J FCCH 20 Hz) and 2.21.4 (6H, m, 3xCH ₂ ).

Intermediate 11 {6R-16-Cyclopentylamino)purin-9-yl-2,2,-dimethyltetrahydro(3aR,6aR)furo[3,4-d][1,3]dioxol-4R-yl}methanol A solution of {2,2-dimethyl-6R-[6-chloropurin-9-yl]-tetrahydro(3aR,6aR)furo[3,4-d][1,3]dioxol-4R-yl}methanol and 50 ml of cyclopentylamine was refluxed for 8 hours. The solution was cooled to ambient temperature, then evaporated in vacuo, and the evaporation residue was applied to a column containing 250 g of silica gel. Elution was carried out with a 20:1 mixture of ethyl acetate and methanol. In this way, 3.87 g of the title compound was obtained as a yellow foam.

NMR δ (DMSO): 8.4 (1H, s, -CH), 8.26 (1H, broad s, CH), 7.85 (1H, broad s, NH), 6.19 1H, d, CH), 5.4 (1H, dd, CH), 5.37 (1H, broad s, OH), 5.03 (1H, dd, CH), 4.57 (1H, broad s, CH), 4.28 (1H, m, CH), 3.60 (2H, m, CH ₂ ), 1.99 (2H, m, CH ₂ ), 1.8-1.55 (9H, 3xCH ₂ + CH ₃ ) and 1.38 (3H, s, CH ₃ ).

12. intermediate

Cyclopentyl-f 9-[2,2-dimethyl-6R-(2,2,2-trifluoroethoxymethyl)-tetrahydro(3aR,6aR)furo[3,4-d][1,3]dioxol-4R-yl]-9H-purin-6-yl)-amine 230 mg of {6R-[6-(cyclopentylamino)-purin-9-yl]-2,2-dimethyl-tetrahydro(3aR,6aR)furo[3,4-d][1,3]dioxol-4R-yl}-methanol were dissolved in 1 ml of tetrahydrofuran, then the resulting solution was treated under nitrogen at 0 °C with 0.23 ml (186 mg) of tri(n-butyl)phosphine and 0.07 ml (92 mg) of 2,2,2-trifluoroethanol, then 232 mg was treated with 1,1’-azadicarbonyldipiperidine. The resulting mixture was stirred at 0 °C for 10 min and then kept at 22 °C for 18 h. The mixture was then kept at 50 °C for 24 h and then cooled to 22 °C. The solvent was evaporated in vacuo. The residue was purified by flash chromatography.

- Purification on 20 g of silica with 33. Ethyl acetate was used as eluent. Thus, 110 mg of the title compound was obtained as a straw-colored foam.

TLC silica gel (ethyl acetate) Rf = 0.45.

Intermediate 3 2,2-Dimethyl-6R-[6-(tetrahydropyran-4-ylamino)purin-9-yl]-tetrahydro(3aR,6aR)furo[3,4-d1[1,3]dioxol-4R-yl)-methanol 2.00 g {2,2-dimethyl-6R-[6chloropurin-9-yl]-tetrahydro(3aR,6aR)furo[3,4-d][1,3]dioxol-4R-yl}-methanol, 926 mg tetrahydropyran-4-ylamine hydrochloride and 2.67 ml diisopropylethylamine were dissolved in 10 ml propan-2-ol. The resulting solution was refluxed under nitrogen for 24 hours and then allowed to cool to ambient temperature. An amber solution was obtained, which was evaporated in vacuo. The brown oil obtained as the evaporation residue was purified by flash chromatography on 115 g of silica using a 195:5 mixture of ethyl acetate and methanol as eluent to give the title compound as a white foam (2.2 g).

TLC _SiO2 (methanol:ethyl acetate = 5:195), Rf = 0.30.

Intermediate 14: 9-2,2-Dimethyl-6R-(2,2,2-trifluoroethoxymethyl)-tetrahydro(3aR,6aR)furo[3,4-di[1,3]dioxol-4R-yl]-9H-purin-6-yl)-(tetrahydropyran-5-yl)-amine 400 mg of {2,2-dimethyl-6R-[6-(tetrahydropyran-4-yl-amino)-purin-9-yl]-tetrahydro(3aR,6aR)furo[3,4-d][1,3]dioxol-4R-yl}-methanol was dissolved in 1 ml of tetrahydrofuran, and the resulting solution was stirred at 0 °C.

- 34 was first treated under nitrogen with 0.38 ml (310 mg) of tri(n-butyl)phosphine and 0.11 ml (153 mg) of 2,2,2-trifluoroethanol, then with 387 mg of 1,1'-azadicarbonyldipiperidine, and the resulting mixture was stirred at 0 °C for 10 minutes. The mixture was then stirred at 22 °C for one hour and at 50 °C for 18 hours, then cooled to 22 °C and the solvent was evaporated in vacuo. The residue was purified by chromatography on 30 g of silica. Elution was carried out with a 0.35:10 mixture of methanol and dichloromethane. This gave a straw-colored oil which was further purified by chromatography on 20 g of alumina using a 7:3 mixture of ethyl acetate and cyclohexane as eluent to give 113 mg of the title compound as a white foam.

TLC SiO ₂ (CH ₂ Cl ₂ :MeOH = 200:7) Rf = 0.31.

15. intermediate

Methanesulfonic acid [6R-(6-chloropurin-9-yl)-2,2-dimethyltetrahydro(3aR,6aR)furof3,4-dine _; 3]dioxol-4R-ylmethyl] ester 500 mg {2,2-dimethyl-6R-[6-chloropurin-9-yl]-tetrahydro(3aR,6aR)furo[3,4-d][1,3]dioxol-4R-yl}methanol was dissolved in 1 ml of dichloromethane, and the resulting solution was treated at 0 °C under nitrogen with 0.32 ml (232 mg) triethylamine and 0.15 ml of methanesulfonyl chloride. The resulting mixture was stirred at 0 °C for 0.5 h, then poured into 20 ml of 8% sodium bicarbonate solution. The organic phase was separated, dried over sodium sulfate and concentrated in vacuo to give the title compound as a white foam (577 mg).

TLC silica gel (ethyl acetate) Rf = 0.43.

16. intermediate

Methanesulfonic acid {6R-[6-(benzyloxy)purin-9-yl)-2,2-dimethyltetrahydro(3aR,6aR)furo[3,4-dl(1,3]dioxol-4R-ylmethyl) ester

1.60 ml (1.675 g) of benzyl alcohol was dissolved in 100 ml of tetrahydrofuran. 626 mg of 60% oily sodium hydride suspension was added to the solution in portions at 0 °C under nitrogen atmosphere, and the resulting mixture was stirred at 0 °C for 0.5 h. Then 5.70 g of methanesulfonic acid [6R-(6-chloropurin-9-yl)-2,2-dimethyltetrahydro(3aR,6aR)furo[3,4-d][1,3]dioxol-4 R-ylmethyl] ester dissolved in 100 ml of tetrahydrofuran was added. The resulting mixture was stirred at 0 °C for 2 h and then at 22 °C for 3 days. Then 100 ml of phosphate buffer (pH = 6.5) and 100 ml of water were added. The resulting mixture was extracted with ethyl acetate. The extracts were combined, dried over sodium sulfate, and the solvent was evaporated in vacuo. In this way, 6.67 g of the title compound was obtained as a straw-colored, viscous, gum-like substance.

TLC S1O2 (ethyl acetate:cyclohexane = 7:3) Rf = 0.35.

17. intermediate

6-(Benzyloxy)-9-[2,2-dimethyl-6R-(2,2,2-trifluoroethoxymethyl)-tetrahydro(3aR,6aR)furoyl3,4-d][1,3]dioxol-4R-yl)-9H-purine

1.13 ml (1.549 g) of 2,2,2-trifluoroethane was treated with 563 mg of a 60% oily suspension of sodium hydride in 50 ml of dimethylformamide under a nitrogen atmosphere, and the resulting mixture was stirred at 22 °C for 0.5 h. To the solution was added 6.67 g of methanesulfonic acid {6R-[6-(benzyloxy)-purin-9yl]-2,2-dimethyl-tetrahydro(3aR,6aR)furo[3,4-d][1,3]dioxo I-4 R-yl-methyl} ester dissolved in 50 ml of dimethylformamide, and the resulting mixture was stirred at 22 °C for 18 h. This

- After 36 h, 100 ml of phosphate buffer (pH = 6.5) and 300 ml of water were added, and the resulting mixture was extracted with ethyl acetate. The extracts were combined, washed first with water, then with aqueous sodium chloride solution, and dried with sodium sulfate. The residue obtained after vacuum evaporation was purified by flash chromatography on 100 g of silica. Eluents were first 1:3 and then 1:2 mixtures of ethyl acetate and cyclohexane. In this way, 1.30 g of the title compound was obtained as a colorless, oily substance.

TLC silica gel (ethyl acetate:cyclohexane = 2:3) Rf = 0.27.

18. intermediate

9-[2,2-Dimethyl-6R-(2,2,2-trifluoroethoxymethyl)-tetrahydro(3aR,6aR)furo[3,4-d][1,3]dioxol-4R-yl]-1,9-dihydropurin-6-one 1.50 g of 6-benzyloxy-9-[2,2-dimethyl-6R-(2,2,2-trifluoroethoxymethyl)-tetrahydro(3aR,6aR)furo[3,4-d][1,3]dioxol-4R-yl]-9H-purine was dissolved in 100 ml of ethanol and the resulting solution was hydrogenated in the presence of 350 mg of 50% water, 10% palladium on carbon catalyst. After 35 min, the mixture was filtered through Hyflo and then carefully washed with methanol. The filtrate and liquids were combined and concentrated in vacuo to give the title compound as a white solid (636 mg).

Mass spectrum: m/z 391 (MH ⁺ ).

19. intermediate

6-Chloro-9-[2,2-dimethyl-6R-(2,2,2-trifluoroethoxymethyl)-tetrahydro(3aR,6aR)furo[3,4-d][1,3]dioxol-4R-yl]-9H-purine 616 mg of 9-[2,2-dimethyl-6R-37-(2,2,2-trifluoroethoxymethyl)-tetrahydro(3aR,6aR)furo[3,4-d][1,3]dioxol-4R-yl]-1,9-dihydropurin-6-one and 193 mg of 4-(dimethylamino)pyridine were dissolved in 6-chloro-9-[2,2,2-trifluoroethoxymethyl]-tetrahydro(3aR,6aR)furo[3,4-d][1,3]dioxol-4R-yl]-1,9-dihydropurin-6-one and 193 mg of 4-(dimethylamino)pyridine, and then 0.44 ml (726 mg) of phosphorus(III) oxychloride was added to the resulting solution under nitrogen atmosphere while stirring. The resulting mixture was refluxed for 0.5 h. Then, approximately 0.2 ml of phosphorus(III) oxychloride was added and the resulting mixture was refluxed for a further 0.5 h, cooled to 22 °C, left to stand for 18 h, and then poured into a mixture of 6 ml of triethylamine and 6 ml of ice while cooling. The aqueous phase was acidified with concentrated hydrochloric acid until pH = 1 and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate and evaporated in vacuo to give 1.3 g of a brown oil which was purified by chromatography on 30 g of Merck 9385 silica. Elution was carried out with a 2:98 mixture of methanol and dichloromethane to give the title compound as a wool-colored foam (73 mg).

TLC silica gel (methanol:dichloromethane = 2.98) Rf = 0.37.

Intermediate 20 (2R,3R,4S,5R)-2-(6-chloropurin-9-yl)-5-(2,2,2-trifluoroethoxymethyl)tetrahydrofuran-3,4-diol 754 mg of 6-chloro-9-[2,2-dimethyl-6R-(2,2,2-trifluoroethoxymethyl)-tetrahydro(3aR,6aR)furo[3,4-d][1,3]dioxo 1-4R-yl]-9H-purine was dissolved in 1 ml of trifluoroacetic acid, and the resulting solution was treated with 1.0 ml of water at -10 °C under a nitrogen atmosphere. The resulting mixture was stirred at a temperature between -10 °C and 0 °C for 1.5 hours. The solvent

- 38 was evaporated under vacuum at 20 °C and the residue was treated with a mixture of dichloromethane, ethanol and ammonia (10:8:1, v/v) (30 ml). The solvent was removed under vacuum to give an oil which was chromatographed on 30 g of silica. A mixture of methanol and dichloromethane (5:95, v/v) was used as eluent. In this way, the title compound was obtained in the form of a colourless foam in the amount of 483 mg (71%) in the form of a colourless foam.

TLC silica gel (methanol:dichloromethane = 5:95) Rf = 0.26.

Intermediate 21 12,2-Dimethyl-6R-[6-(tetrahydropyran-4-yl-amino)-purin-9-yltetrahydro(3aR,6aR)furof3,4-d1[1,3]dioxol-4R-yl}-methanol

A mixture of 8.25 g of benzoic acid [3R,4R-bis(benzoyloxy)-5R-(2,6-dichloropurin-9-yl)tetrahydrofuran-2R-yl] ester, 1.92 g of tetrahydropyran-4-ylamine hydrochloride, 5.5 ml of diisopropylethylamine and 100 ml of isopropanol was refluxed under nitrogen for 1.5 hours. The resulting solution was evaporated in vacuo and the residue was treated with 4.5 g of potassium carbonate dissolved in 150 ml of methanol. The mixture was kept at 21 °C for 24 hours, then 4.5 g of potassium carbonate was added and stirring was continued at 21 °C for 64 hours. The solvent was evaporated in vacuo and the residue was absorbed onto 250 g of silica before purification by flash chromatography. Elution was carried out with a 90:10:1 mixture of dichloromethane, methanol and ammonia. This gave 3.7 g of an off-white foam which was dissolved in 60 ml of acetone. The resulting mixture was treated with 2.0 g of p-toluenesulfonic acid monohydrate and 6 ml of 2,2-dimethoxypropane. The resulting mixture was stirred at 22 °C overnight. The white

·..· : .:. „.· ··»* - 39 The suspension was evaporated in vacuo and the residue was partitioned between 8% aqueous sodium bicarbonate solution and ethyl acetate. The aqueous phase was further extracted with ethyl acetate, and the combined organic extracts were washed first with water and then with aqueous sodium chloride solution, dried over sodium sulfate and evaporated in vacuo. The resulting foam was purified by flash chromatography on 100 g of silica using ethyl acetate as eluent. In this way, 3.49 g of the title compound was obtained as a colorless foam.

TLC silica gel (ethyl acetate) Rf = 0.23.

Intermediate 22: 9-[6R-[3-(tert-butyl-dimethyl-silanyloxy)-propoxymethyl]-2,2-dimethyl-tetrahydro(3aR,6aR)furoyl-3,4-diyl _] -3-dioxol-4R-[1H-2-chloro-9H-purin-6-yl]-(tetrahydropyran-4-yl)-amine 720 mg of tert-butyl-(3-iodo-propoxy)-dimethylsilane was dissolved in 100 ml of anhydrous dimethylformamide, and then 150 mg of 60% oily sodium hydride dispersion was added to the resulting solution under a nitrogen atmosphere and with ice cooling. After one hour, the yellow mixture was treated with 540 mg of {2,2-dimethyl-6R-[6-(tetrahydropyran-4-ylamino)-purin-9-yl]-tetrahydro(3aR,6aR)furo[3,4-d][1,3]dioxo I -4 Ri I}-methanol and the resulting mixture was stirred at ambient temperature for 17 hours. 0.5 ml of acetic acid was then added and the resulting mixture was stirred for one hour and then poured into 15 ml of aqueous sodium chloride solution. The aqueous mixture was extracted with ethyl acetate and the combined organic extracts were washed first with water and then with aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. In this way, a yellow, oily substance was obtained, which was placed in a 5 cm diameter, silica-filled • · · · · · · · *··* I .1. ·Ί·

- Purification was carried out by flash chromatography on a 40 column. A 95:5:1 mixture of toluene, ethanol and triethylamine (v/v) was used as the eluent. The elution was repeated on a 3 cm diameter column to obtain 269 mg of a pale yellow, oily substance.

TLC silica gel (toluene:ethanol:triethylamine = 90:10:1) Rf = 0.39.

23. intermediate

3-{6R-[2-Chloro-6-(tetrahydropyran-3-yl-amino)-purin-9-yl]-2,2-dimethyl-tetrahydro(3aR,6aR)furo[3,4-d][1,3]dioxol-4R-yl-methoxy)-proan-1-ol 420 mg of (9-{6R-[3-(tert-butyl-dimethyl-silanyloxy)-propoxymethyl]-2,2-dimethyl-tetrahydro(3aR,6aR)furo[3,4-d][1,3]dioxol-4R-yl}-2-chloro-9H-purin-6-yl)-(tetrahydropyran-4-yl)-amine were dissolved in 1 ml of anhydrous tetrahydrofuran, and the resulting solution was treated with 12 ml of 1 M tetra-(n-butyl-ammonium fluoride solution in tetrahydrofuran. The resulting yellow solution was stirred at ambient temperature for 3 hours. The solution was evaporated in vacuo and the residue was purified by flash chromatography on a 20 g silica column using a 90:10:1 mixture of toluene, ethanol and triethylamine as eluent to give the title compound as a colourless gum (299 mg).

TLC silica gel (toluene:ethanol:triethylamine = 90:10:1) Rf = 0.28.

Intermediate 24 12-Chloro-9-[6R-('3-fluoro-propoxymethyl)-2,2-dimethyl-tetrahydro(3aR,6aR)furo[3,4-d][1,31dioxo l-4R-yl1-9H-purin-6-yl)-(tetrahydropyran-4-yl)-amine 280 mg were dissolved in ml of dichloromethane 3-{6R-[2-chloro-6-(tetrahydropyran-4-ylamino)purin-9-yl]-2,2-dimethyltetrahydro(3aR,6aR)JI · ·**··» : .t. -t·

- 41 furo[3,4-d][1,3]dioxol-4R-ylmethoxy}-propan-1-ol, then the resulting solution was treated with 0.13 ml diethylaminosulfur trifluoride. The resulting pale yellow solution was stirred at 22 °C for 17 hours. The reaction mixture was partitioned between 10 ml ethyl acetate and 10 ml 2 N sodium carbonate solution. The phases were separated and the aqueous phase was back-extracted with 10 ml ethyl acetate. The organic extracts were combined, washed with brine, dried over sodium sulfate and evaporated. The resulting pale yellow, oily substance was purified by flash chromatography on 30 g silica. A 95:5:1 mixture of toluene, ethanol and triethylamine (v/v) was used as eluent. In this way, 173 mg of the title compound was obtained as an off-white foam.

TLC silica gel (toluene:ethanol:triethylamine = 90:10:1) Rf = 0.41.

25, intermediate (9-[6R-(3-Fluoro-propoxymethyl)-2,2-dimethyl-tetrahydro(3aR,6aR)furo[3,4-d]yl-1,31dioxol-4R-yl-9H-purin-6-yl}(tetrahydropyran-4-yl)-amine

A suspension of 120 mg of {2-chloro-9-[6R-(3-fluoropropoxymethyl)-2,2-dimethyltetrahydro(3aR,6aR)furo[3,4-d][1,3]dioxol-4R-yl]-9H-purin-6-yl}(tetrahydropyran-4-yl)-amine, 180 mg of a 50% aqueous paste of 5% palladium on carbon, 120 mg of ammonium formate and 25 ml of methanol was refluxed under nitrogen for 18 hours. The suspension was then filtered through hyflo, concentrated in vacuo and the residue partitioned between 5 ml of ethyl acetate and 5 ml of water. The organic phase was back-extracted with 5 ml of ethyl acetate. The organic extracts were combined, washed with brine, dried over sodium sulfate, and evaporated in vacuo. The residue was

- 42 * . * * · · · · g ♦ The resulting semi-solid was treated with about 5 ml of chloroform, the resulting cloudy suspension was filtered through a pad of raw cotton, and the filtrate was evaporated in vacuo to give the title compound as a white foam (81 mg).

TLC silica gel (toluene:ethanol:triethylamine = 90:10:1) Rf = 0.33.

Example 1

Preparation of N-CTetrahydropyran^-iD-S’-O-trifluoromethyladenosine 170 mg of acetic acid [4R-acetoxy-2R-(6-chloropurin-9-yl)-5R-(trifluoromethoxymethyl)tetrahydrofuran-3R-yl] ester were heated in 100 ml isopropanol for 20 hours under reflux with 235 mg of tetrahydropyran-4-ylamine hydrochloride and 0.35 ml of diisopropylethylamine. After cooling, the solvent was evaporated in vacuo, then 15 ml of saturated methanolic ammonia solution was added, and the resulting solution was left to stand at 22 °C for 3 hours. The solvent was removed in vacuo, and the crude product was triturated with 6 ml of ether. In this way, 96 mg of the title compound was obtained as a colorless powder.

Mass spectrum: m/z 420 (MH ⁺ ).

Values measured by microanalysis:

Found, %; C 45.7; H 4.9; N 16.3.

Based on the formula _Ci6H20F3N5O5 : calculated, %: C 45.8; H 4.8; N 16.7;

Example 2

Preparation of N-(2-Pyridin-4-yl-ethyl)-5'-O-trifluoromethyl-adenosine mg (2R,3R,4S,5R)-2-(6-chloro-purin-9-yl)-5-(trifluoromethoxymethyl)-tetrahydrofuran-3,4-diol, 58 mg 2-pyridin-4-yl-ethylamine, 0.124 ml

- A mixture of 43 g of diisopropylethylamine and 5 ml of isopropanol was heated in a reaction vessel at 80 °C for 17 hours. The solution was evaporated under a stream of nitrogen and purified by autopreparative high-performance liquid chromatography to give the title compound as a colorless solid (16 mg).

Mass spectrum: m/z 441 (MH ⁺ ).

HPLC Rt = 10.39 min.

Example 3

Preparation of N-(exo-Bicyclo[2.2.1 ]hept-2-yl)-5’-O-(trifluoromethyl)-adenosine mg of acetic acid [4R-acetoxy-2R-(6-chloropurin-9-yl)-5R-(trifluoromethoxymethyl)-tetrahydrofuran-3R-yl]-ester and 55 mg of (±)-exo-norbornylamine and 0.128 ml of diisopropylethylamine were kept in a reaction vessel for 65 hours in 7 ml of isopropanol at 80 °C. The solutions were concentrated to a small volume under a nitrogen stream, then saturated methanolic ammonia solution was added, and the resulting solution was left to stand for 3 hours, then evaporated in vacuo, and the evaporation residue was purified by chromatography using an SPE cartridge. The eluent was first chloroform, then a 10:1 mixture of ethyl acetate and methanol. In this way, 51 mg of the title compound was obtained as a colorless foam.

Mass spectrum: m/z 430 (MH ⁺ ).

LCMS Rt = 4.16 min.

Example 4

Preparation of 5’-Q-(Trifluoromethyl)adenosine

- 44 53 mg of acetic acid [4R-acetoxy-2R-(6-chloro-purin-9-yl)-5R-(trifluoromethoxymethyl)-tetrahydrofuran-3R-yl] ester was dissolved in 5 ml of saturated methanolic ammonia solution, and the resulting solution was left to stand at 22 °C for 3 days. The material was blown off under a nitrogen atmosphere, and the residue was purified by flash chromatography on 10 g of silica. A 9:1 mixture of dichloromethane and methanol (v/v) was used as the eluent. In this way, 8.3 mg of the title compound was obtained as a transparent gummy substance.

Mass spectrum: m/z 336 (MH ⁺ ).

LCMS Rt = 3.44 min.

Example 5

Preparation of 2-[9-[3R,4S-Dihydroxy-5R-(trifluoromethoxymethyltetrahydrofuran-2R-1H-9H-purin-6-ylamino}ethanesulfonic acid methylamide mg of acetic acid [4R-acetoxy-2R-(6-chloropurin-9-yl)-5R-(trifluoromethoxymethyl)tetrahydrofuran-3R-yl] ester was treated in 5 ml of isopropanol with 85 mg of 2-aminoethanesulfonic acid methylamide and 0.211 ml of diisopropylethylamine, then the resulting mixture was kept in a reaction vessel at 80 °C for 65 hours. After the mixture had cooled, the solvent was removed in a nitrogen stream, then saturated methanolic ammonia solution was added. The resulting solution was left to stand at 22 C for 3 hours, then 5 ml was treated with 8% sodium bicarbonate solution and 5 g of silica. The resulting mixture was evaporated to dryness in vacuo. The resulting solid mixture was applied to a column containing 20 g of silica and eluted with dichloromethane and methanol (20:1-5:1) in a volume ratio. The colorless solid thus obtained was recrystallized from 2 ml of methanol to give the title compound as colorless crystals (20 mg).

- Compound according to 45.

Mass spectrum: m/z 457 (MH ⁺ ).

LCMS Rt = 3.62 min.

, example

Preparation of N-Cyclopentyl-{9-[2,2-dimethyl-6R-(2,2,2-trifluoroethoxymethyl)-tetrahydro(3aR,6aR)furo[3,4-d][1,3]dioxol-4R-yl]-9H-purin-6-yl}-amine was dissolved in 100 mg of trifluoroacetic acid, then the resulting solution was treated with 0.2 ml of water at -10 °C under a nitrogen atmosphere, and the resulting mixture was stirred at a temperature between -10 °C and 0 C for 4 hours. The solvent was removed in vacuo at 20 °C, and the residue was treated with a 10:8:1 mixture of dichloromethane, ethanol and ammonia. The solvent was evaporated in vacuo and the residue was purified by flash chromatography on 15 g of silica, eluting with a 100:8:1 mixture of dichloromethane, ethanol and ammonia to give the title compound as a colourless solid (60 mg), mp 74-76 °C.

TLC silica gel (dichloromethane:ethanol:ammonia = 100:8:1) Rf = 0.29.

Mass spectrum: m/z 418 (MH ⁺ ).

example

Preparation of N-(Tetrahydropyran-4-yl)-5'-O-(2,2,2-trifluoroethyl)-adenosine 90 mg of {9-[2,2-dimethyl-6R-(2,2,2-trifluoroethoxymethyl)-tetrahydro(3aR,6aR)furo[3,4-d][1,3]dioxol-4R-yl]-9H-purin-6-yl}-(tetrahydropyran-4-yl)-amine were dissolved in 100 ml of trifluoroacetic acid, and the resulting solution was then

- 46 dat was treated with 0.2 ml of water under nitrogen at -10 °C. The resulting mixture was stirred at -10 °C to 0 °C for 4 hours. The solvent was evaporated in vacuo and the residue was purified by chromatography on silica at 20 °C. The residue was treated with 15 ml of a mixture of dichloromethane, ethanol and ammonia (10:8:1 by volume) and the solvent was evaporated in vacuo (15 g). Elution was carried out with a mixture of dichloromethane, ethanol and ammonia (75:8:1 by volume). In this way, 69 mg of the title compound were obtained as a white solid, melting at 80-82 °C.

TLC silica gel (dichloromethane:ethanol:ammonia = 75:8:1) Rf = 0.2.

Example 8

Preparation of N-(2R-Hydroxycyclopent-(R)-yl)-5 ^, -O-(2,2,2-trifluoroethyl)adenosine

50 mg of (2R,3R,4S,5R)-2-(6-chloropurin-9-yl)-5-(2,2,2-trifluoroethoxymethyl)tetrahydrofuran-3,4-diol in 5 ml of isopropanol were treated under nitrogen with 82 mg of (1 R,2R)-2-aminocyclopentanol and 0.28 ml (210 mg) of diisopropylethylamine, and the resulting mixture was refluxed for 18 hours. The solvent was evaporated in vacuo and the residue was purified by chromatography on 30 g of silica. The elution was carried out with a 100:10:1 mixture of dichloromethane, ethanol and ammonia. In this way, 116 mg of the title compound was obtained as a wool-colored solid, melting point 164-166 °C.

TLC silica gel (dichloromethane:ethanol:ammonia = 100:10:1) Rf =

0.32.

Example 9

Preparation of N-(4-Fluorophenyl)-5'-O-(2,2,2-trifluoroethyl)adenosine

125 mg of (2R,3R,4S,5R)-2-(6-chloropurin-9-yl)-5-(2,2,2-trifluoroethoxymethyl)-tetrahydrofuran-3,4-diol in 5 ml of isopropanol were treated under nitrogen with 0.08 ml (90 mg) of 4-fluoroaniline and 0.28 ml (210 mg) of diisopropylethylamine and the mixture was refluxed for 24 hours. The mixture was cooled to 22 °C and filtered. The filter cake was washed with 2 ml of isopropanol and 15 ml of ether and the solid was dried in vacuo to give the title compound as a white solid (70 mg), mp 214-215 °C.

TLC silica gel (dichloromethane:ethanol:ammonia = 100:10:1) Rf = 0.36.

0, example

Preparation of 5'-O-(3-Fluoropropyl)-N-(tetrahydropyran-4-yl)adenosine

In 0.8 ml of ice-cold trifluoroacetic acid, 79 mg of {9-[6R(3-Fluoro-propoxymethyl)-2,2-dimethyl-tetrahydro(3aR,6aR)furo[3,4-d][1,3]d i oxe I-4 R-y l]-9 H-purin-6-y I}-(tetrahydripyran-4-y I )-amine were dissolved. The resulting solution was treated with 0.08 ml of water and stirred at 0 to 5 °C for one hour. The excess trifluoroacetic acid was removed in vacuo at 30 °C, and the residue was purified by flash chromatography on a column filled with 10 g of silica. A 94:6:1 mixture of dichloromethane, methanol and ammonia was used as eluent. In this way, 52 mg of the title compound was obtained as a colorless foam.

- 48 Mass spectrum: m/z 412 (MH ⁺ ).

TLC silica gel (dichloromethane:methanol:ammonia = 94:6:1) Rf = 0.14.

Example 11

Preparation of 2-chloro-5'-(3-fluoropropyl)-N-(tetrahydropyran-4-yl)adenosine

50 mg of {2-chloro-9-[6R-(3fluoropropoxymethyl)-2,2-dimethyltetrahydro(3aR,6aR)furo[3,4-d][1,3]dioxol-4R-yl]-9H-purin-6-yl}-(tetrahydropyran-4-yl)-amine were dissolved in 0.5 ml of trifluoroacetic acid and the resulting solution was treated with 0.05 ml of water at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. The excess trifluoroacetic acid was removed in vacuo at 30 °C and the residue was purified by flash chromatography on 10 g of silica. A 94:6:1 mixture of dichloromethane, methanol and ammonia was used as eluent. In this way, 32 mg of the title compound was obtained as a colorless foam.

TLC silica gel (dichloromethane:methanol:ammonia = 94:6:1) Rf = 0.18.

Mass spectrum: m/z 446 (MH ⁺ ).

The compounds of the following examples were prepared in a similar manner.

Example 12

Preparation of N-(2S-Fluorocyclopent-(S)-yl)-5’-O-trifluoromethyladenosine

The title compound was prepared from intermediate 6.

Mass spectrum: m/z 422 (MH ⁺ ).

- 49 HPLC R _t = 19.24 min.

Example 3

Preparation of N-(Tetrahydrothiopyran-4-yn-5- ^yl) -O-(trifluoromethyl)adenosine

The title compound was prepared from intermediate 6.

Mass spectrum: m/z 436 (MH ⁺ ).

HPLC Rt = 17.61 min.

Example 14

Preparation of N-(3,4-Difluorophenyl)-5'-Q-(trifluoromethyl)adenosine

The title compound was prepared from intermediate 6.

Mass spectrum: m/z 448 (MH ⁺ ).

HPLC Rt = 25.44 min.

Example 15

Preparation of N-(3-Fluorophenyl)-5’-O-(trifluoromethyl)adenosine

The title compound was prepared from intermediate 6.

Mass spectrum: m/z 430 (MH ⁺ ).

HPLC _Rt = 24.65 min.

Example 16

Preparation of N-(1,1-Dioxo-hexahydro-1.delta. 6-thiopyran-4-yl)-5'-Q-(trifluoromethyl)-adenosine

The title compound was prepared from intermediate 5.

LC = MS Rt = 3.62 min.

Mass spectrum: m/z 468 (MH ⁺ ).

Example 7

Preparation of N-tert-Butyl-5'-O-(trifluoromethyl)-adenosine

The title compound was prepared from intermediate 5.

LC/MS _Rt = 4.12 min.

Mass spectrum: m/z 392 (MH ⁺ ).

Example 8

Preparation of 4-[9-(3R,4S-Dihydroxy-5R-(trifluoromethoxymethyl)-tetrahydrofuran-2R-yl)-9H-purin-6-yl-amino-1-piperidine-1-carboxylic acid ethyl ester

The title compound was prepared from intermediate 5.

Mass spectrum: m/z 491 (MH ⁺ ).

NMR δ (CDCl3) 8.25 (1H, s, CH [in heterocyclic group]), 8.15 (1H, s, CH [in heterocyclic group]), 6.05 (1H, d, CH), 4.7 (1H, m, CH), 4.0-4.5 (9H, m, 5xCH + 2xCH ₂ ), 3.1 (2H, broad t, CH ₂ ), 2.08 (2H, broad d, 2xCH), 1.55 (2H, broad q, 2xCH) and 1.28 (3H, t, CH ₃ ).

Example 9

Preparation of N-(2S-Hydroxycyclopent-(S)-iD-5’-O-(trifluoromethyl)adenosine

The title compound was prepared from intermediate 5.

LC/MS Rt = 3.71 min.

Mass spectrum: m/z 420 (MH ⁺ ).

Example 20

Preparation of N-(rel-2,3-Dihydroxypropyl)-5’-O-(trifluoromethyl)adenosine

The title compound was prepared from intermediate 5.

- 51 LC/MS Rt = 3.43 min.

Mass spectrum: m/z 410 (MH ⁺ ).

Example 21

Preparation of N-tetrahydrofuran-SR-iD-S'-O-trifluoromethyladenosine

The title compound was prepared from intermediate 5.

LC/MS _Rt = 3.62 min.

Mass spectrum: m/z 406 (MH ⁺ ).

Example 22

Preparation of N-(Tetrahydrofuran-3S-iD-5’-O-(trifluoromethyl)adenosine

The title compound was prepared from intermediate 5.

LC/MS _Rt = 3.62 min.

Mass spectrum: m/z 406 (MH ⁺ ).

Example 23

Preparation of N-[2-[9-(3R,4S-Dihydroxy-5R-(trifluoromethoxymethyl)tetrahydrofuran-2R-yl)-9H-purin-6-ylamino]ethyl]acetamide

The title compound was prepared from intermediate 5.

LC/MS Rt = 3.53 min.

Mass spectrum: m/z 421 (MH ⁺ ).

Example 24

Preparation of 4-[9-(3R,4S-Dihydroxy-5R-trifluoromethoxymethyl-tetrahydrofuran-2R-yl)-2-methyl-9H-purin-6-yl-aminol-piperidine-1-carboxylic acid ethyl ester

The title compound was prepared from intermediate 5.

- 52 LC/MS R _t = 3.97 min.

Mass spectrum: m/z 505 (MH ⁺ ).

Example 25

Preparation of 2-Methyl-N-(tetrahydropyran-4-yl)-5 ^, -Q-trifluoromethyladenosine

LC/MS _Rt = 3.72 min.

Mass spectrum: m/z 434 (MH ⁺ ).

Example 26

Preparation of N-(2-Chloro-4-fluorophenyl)-5’-O-(trifluoromethyl)-adenosine A mixture containing 0.16 g of acetic acid [4R-acetoxy-2R-(6-chloropurin-9-yl)-5R-(trifluoromethoxymethyltetrahydrofuran-3R-yl] ester, 0.26 ml of 2-chloro-4-fluoroaniline, 8 mg of palladium acetate, 33 mg of R-BINAP [R-(+)-2,2’-bis(diphenylphosphino)-1,Γ-binaphthyl], 0.16 g of cesium carbonate and 1.2 ml of toluene was kept in a reaction vessel at 85-91 °C for 16 hours. The reaction mixture was cooled to ambient temperature, then the reaction was quenched by adding 20 ml of water. The resulting mixture was divided into 3x50 ml was extracted with dichloromethane. The organic extracts were dried over magnesium sulfate and evaporated in vacuo. The residue obtained was purified by flash chromatography on a Biotage column packed with 8 g of silica. Elution was carried out with mixtures of cyclohexane and ethyl acetate (9:1-6:4) in a volume ratio. The resulting clear oil was dissolved in 1 ml of methanol, the solution was cooled to a temperature between 0 °C and 5 °C, and then treated with 0.05 ml of tert-butylamine. The mixture was kept at this temperature for one hour and then evaporated to dryness in vacuo. In this way, 67 mg of the title compound was obtained as a white solid.

- 53 LC/MS Rt = 3.04 min.

Mass spectrum: m/z 464 (MH ⁺ ), 466 (MH ⁺ +2).

Example 27

Preparation of N-(4-Chloro-2-fluorophenyl)-5'-O-(trifluoromethyl)adenosine

It was prepared from intermediate 5 in a similar manner to the procedure variant of Example 26.

LC/MS _Rt = 3.16 min.

Mass spectrum: m/z 464 (MH ⁺ ), 466 (MH ⁺ +2).

Marker gene experiments

Agonist activity was measured in Chinese hamster ovary (CHO) cells containing the CRE/SPAP/HYG (CRE = cyclic AMP responsive element; SPAP = placentally secreted alkaline phosphatase; HYG = hygromycin resistance) marker gene elements, which produced SPAP upon stimulation by cAMP concentrations. A cell line was used that produced SPAP upon stimulation by cAMP levels. The cells were plated in 96-well plates in culture medium and incubated at 37°C for one hour. To measure potency, agonists were added to the appropriate wells at concentrations of approximately 10' ¹ °-10' ⁵ M. After 15 minutes, cAMP concentrations were increased by adding forskolin at a maximum concentration. All cells were then incubated for an additional 5 hours at 37 °C and then cooled to ambient temperature. A substrate (p-nitrophenol phosphate, pNPP) was then added to the phosphatase, which was converted into a colored chemical by SPAP, and the 96-well plates were read in a plate reader. From the read data, we were able to

- 54 to measure the concentration dependence of the inhibitory effect of a given agonist on forskolin-stimulated SPAP production. One of the agonists tested in each 96-well plate was a standard non-selective agonist, N-ethylcarboxamidoadenosine (NECA), and the potency of all tested agonists was expressed relative to the NECA samples.

(ECR = Equipotential Concentration Ratio with respect to NECA = 1.)

Results

Table 1: Biological data (A1, A3 receptor, ECR analysis of the receptor gene)

Example number A1 A3 1. 8.40 >129 2. 185.5 - 3. 5.60 143.5 4. 80.7 81.6 5. 33.2 >212 6. 8.70 7.7 7. - - 8. 239.40 - 9. 298 19.7 10. - - 11. - - 12. 1.87 >226 13. 11.1 >276 14. 20.50 197.3 15. 23.2 - 16. 79.50 >207 17. 138.8 >207 18. 5.32 >202 19. 12.10 >150 20. ________24.10________ ______ 284.5 i

Claims (28)

*·.· ‘ϊ. :·Τ 1. Adenosine derivatives having the general formula (I) - R ² represents a C 1-3 alkyl group, a halogen atom or a hydrogen atom; - R ³ represents a straight or branched fluorinated alkyl group having 1-6 carbon atoms; - R ¹ is (1) a group of the general formula -(alk) _n -(C 3-7 cycloalkyl)- including bridged cycloalkyl groups - where alk is an alkylene group having 1-3 carbon atoms and n is 0 or 1 which may optionally be substituted by one or more substituents, namely a hydroxyl group, a halogen atom and/or a C 1-3 alkoxy group; - 2-chloro-5'-O-(3-fluoropropyl)-N-(tetrahydropyran-4-yl)adenosine; - N-cyclopentyl-5'-O-(2,2,2-trifluoroethyl)-adenosine; - N-(tetrahydropyran-4-yl)-5'-O-(2,2,2-trifluoroethyl)adenosine; - N-(2R-hydroxycyclopent-(R)-yl)-5'-O-(2,2,2-trifluoroethyl)adenosine; and - N-(4-fluorophenyl)-5'-O-(2,2,2-trifluoroethyl)adenosine. - 2-methyl-N-(tetrahydro-pyran-4-yl)-5'-O-(trifluoromethyl)-adenosine; - 2-{9-[3R,4S-dihydroxy-5R-(trifluoromethoxymethyl)tetrahydrofuran-2R-yl]-9H-purin-6-ylamino}ethanesulfonic acid methylamide; 2. Among the adenosine derivatives according to claim 1, compounds of general formula (I) containing a C1-C3 fluoroalkyl group in place of the R ³ substituent. (2) a 4-6-membered, at least one heteroatom containing oxygen, nitrogen and/or sulfur, optionally with one or more substituents, namely a C1-C3 alkyl group, a (C1-C4 alkyl)-CO2- group, a (C1-C3 alkyl)-carbonyl group, a (C1-C3 alkyl)-(= 0) _n -S- group, a group of the general formula R ^b R ^a NCO - in which R ^a and R ^b are - 56 se independently of each other are hydrogen atoms or alkyl groups of 1-3 carbon atoms - and/or aliphatic heterocyclic groups containing rings substituted with = O, with the proviso that if the heterocyclic ring contains a sulfur atom, this sulfur atom may optionally be substituted with ( = O) _n , in which n is 1 or 2; 3. The adenosine derivatives according to claim 2, wherein R ³ - Compounds of general formula (I) containing a fluoromethyl group at position 58. (3) a straight or branched carbon chain of 1-12 carbon atoms, optionally containing one or more oxygen atoms, a group of the general formula S(=O) _n - n is 0, 1 or 2 - or a nitrogen atom, optionally substituted with one or more phenyl groups, halogen atoms, hydroxyl groups and/or a group of the general formula NR ^a R ^b - both R ^a and R ^b are alkyl groups of 1-3 carbon atoms or hydrogen atoms - optionally substituted alkyl group; - 4-{9-[3R,4S-dihydroxy-5R-(trifluoromethoxymethyl)-tetrahydrofuran-2R-yl]-2-methyl-9H-purin-6-ylamino}-piperidine-1-carboxylic acid ethyl ester, - 4-{9-[3R,4S-dihydroxy-5R-(trifluoromethoxymethyl)tetrahydrofuran-2R-yl]-9H-purin-6-ylamino}-piperidine-1-carboxylic acid ethyl ester; - N-(2S-hydroxycyclopent-(S)-yl)-5'-O-(trifluoromethyl)adenosine; - N-(rel-2,3-dihydroxypropyl)-5'-O-(trifluoromethyl)adenosine; - N-(tetrahydrofuran-3R-yl)-5'-O-(trifluoromethyl)-adenosine; - N-(tetrahydrofuran-3S-yl)-5'-O-(trifluoromethyl)adenosine; - N-{2-[9-[3R,4S-dihydroxy-5R-(trifluoromethoxymethyl)tetrahydrofuran-2R-yl]-9H-purin-6-ylamino]ethyl}-acetamide; 4. Among the adenosine derivatives according to claim 1, compounds of general formula (I) wherein R ³ is a trifluoromethyl group. (4) a fused bicyclic aromatic ring, in which B is a 5- or 6-membered heterocyclic aromatic group containing one or more oxygen atoms, nitrogen atoms or sulfur atoms; this bicyclic group is linked to the nitrogen atom of the general formula (I) through one of the ring atoms of ring A, and ring B is optionally substituted with a (C1-C3 alkyl)-CO2 group; - 5'-O-(3-fluoropropyl)-N-(tetrahydropyran-4-yl)-adenosine; - 5'-O-(trifluoromethyl)adenosine; 5. Among the adenosine derivatives according to any one of claims 1-4, compounds of general formula (I) wherein the R ² substituent is a hydrogen atom, a methyl group or a halogen atom. (5) a phenyl group optionally substituted with one or more substituents, namely a halogen atom, an HSO ₃ group, an HO-(alk) _n group, a cyano-(alk) _n group, a (C 1-6 alkyl)-(0) _n group optionally substituted with one or more halogen atoms, a nitro-(alk) _n group, a R ^c CO ₂ -(alk) _n -(O) _m group, a R ^c R ^d - with -CON-(alk) _n -group, R ^c with CO-(alk)n-group, R ^e with SO-(alk)n-group, R ^e with SO2-(alk)n-group, R°R ^d SO2N*··· :* J. »> ^: ·β· - 57 - -(alk) _n group, R ^c O-(alk)n group, R ^e SO2NH-(CO) _m -(alk) _n group, R ^c CONH-(alk)n group and/or NR ^c R ^d -(alk)n group, where m is 0 or 1; n is 0 or 1; alk represents a C1-6 alkylene group or a C2-6 alkenyl group; 6. Among the adenosine derivatives according to claim 5, compounds of general formula (I) wherein R ² is hydrogen, methyl or chlorine. (6) a phenyl group optionally substituted with a substituted 5- or 6-membered heterocyclic aromatic group, wherein said heterocyclic aromatic group is optionally substituted with a C1-3 alkyl group or a group of the general formula NR ^c R ^d ; R ^c and R ^d are - independently of each other - hydrogen atom or alkyl group having 1-3 carbon atoms; or in the case of a group of the general formula NR ^c R ^d , R° and R ^d together with the nitrogen atom may form a 5- or 6-membered heterocyclic ring, which may optionally contain other heteroatoms and may optionally be substituted with one or more alkyl groups having 1-3 carbon atoms; and R ^e represents a C 1-3 alkyl group -, and salts and solvates of the adenosine derivatives of the general formula (I), in particular physiologically acceptable solvates and salts thereof. 7. Among the adenosine derivatives according to any one of claims 1-6, those compounds in which in the general formula (I) R ¹ represents an (alk) _n -(C 3-6 cycloalkyl) group, in which n represents 0 or 1, and the cycloalkyl group is unsubstituted or substituted by at least one halogen atom and/or hydroxyl group. 8. Among the adenosine derivatives according to claim 7, those compounds in which n in general formula (I) is 0. 9. Among the adenosine derivatives according to claim 8, those compounds in which the cycloalkyl group in the general formula (I) is monosubstituted by a hydroxyl group or a fluorine atom. 10. Among the adenosine derivatives according to any one of claims 7-9, those compounds in which the cycloalkyl ring in the general formula (I) consists of 5 carbon atoms. 11 10. Among the adenosine derivatives according to any one of claims 1-6, those compounds in which in the general formula (I) the R ¹ substituent is an unsubstituted or substituted aliphatic - 59 heterocyclic group, the substituent of which may be a (C1-C4 alkyl)-CO ₂ group, a (C1-C3 alkyl)-carbonyl group, a (C1-C3 alkyl)-(=O) _n -S-group or a group of the general formula R ^a R ^b NCO- - R ^a and R ^b are as defined above - and in the case where the ring contains an S heteroatom, this sulfur atom may optionally be replaced by (=O) _n , if n is 0, 1 or 2. 12. Among the adenosine derivatives according to claim 11, those compounds in which the heterocyclic ring in the general formula (I) is unsubstituted or substituted with (C1-C4 alkyl)-CO ₂ groups, or - in the case where the heteroatom is a sulfur atom - the ( = O) _n substituent is attached to this sulfur atom in the heterocyclic ring, or - in an even more preferred case - this sulfur atom in the ring is unsubstituted. 13. Among the adenosine derivatives according to claim 12, those compounds in which the sulfur atom in the heterocycle is unsubstituted. 14. Among the adenosine derivatives according to claim 11, those compounds in which the aliphatic heterocyclic group is unsubstituted, or if it is substituted with a (C1-C4 alkyl)-CO ₂ group and the heteroatom is a nitrogen atom, then this substituent is directly attached to the nitrogen atom of the ring. 15. The adenosine derivatives according to any one of claims 11-15, wherein the heterocyclic ring is 5 or 6-membered and - more preferably - contains an oxygen atom, a nitrogen atom or a sulfur atom as the heteroatom. 16. Among the adenosine derivatives according to any one of claims 1-6, those compounds whose R ¹ substituent is a straight or branched alkyl group having 1-5 carbon atoms, in which chain there is at least one S(=O) _n group - n is 0 • * Λ* ' *** * * - ? ./. „-·'·/ - 60 or 1 - and/or substituted with a nitrogen atom. 17. Among the adenosine derivatives according to claim 16, those compounds which are substituted in their chain by a group in which in the general formula S(=O) _{n n} n is 1 or 2. 18. The adenosine derivatives according to any one of claims 15-17, wherein the alkyl group is unsubstituted or substituted by at least one hydroxyl group. 19. The adenosine derivatives according to any one of claims 1-6, wherein the R ¹ substituent is a phenyl group substituted with one or more hydroxyl groups and/or halogen atoms. 20. The adenosine derivatives according to claim 19, wherein the phenyl group is disubstituted at the 2,4-positions. 21. The adenosine derivatives according to claim 20, wherein both substituents of the phenyl group are halogen atoms. 21. 10.90 >175 22. Among the adenosine derivatives according to claim 21, those compounds in which the phenyl group is substituted at the 2-position with a chlorine atom and at the 4-position with a fluorine atom. 22. 10.40 >63 23. The adenosine derivatives according to claim 1, which are the following compounds: - N-(tetrahydropyran-4-yl)-5'-O-(trifluoromethyl)adenosine; - N-(2-pyridin-4-yl-ethyl)-5'-O-(trifluoromethyl)-adenosine,· - N-[2S-fluorocyclopent-(S)-yl]-5'-O-(trifluoromethyl)adenosine, - N-(tetrahydrothiopyran-4-yl)-5'-O-(trifluoromethyl)-adenosine; - N-(3,4-difluorophenyl)-5'-O-(trifluoromethyl)adenosine; - N-(3-fluorophenyl)-5'-O-(trifluoromethyl)adenosine; - N-(exo-bicyclo[2.2.1]hept-2-yl)-5'-O-(trifluoromethyl)-adenosine; *·'* *♦♦· « ♦ • * ·· · • · · > *. ’ · ί ' - 61 - N-(1,1-dioxo-hexahydro-1.delta.6-thiopyran-4-yl)-5'-O-(trifluoromethyl)-adenosine; - N-(tert-butyl)-5'-O-(trifluoromethyl)adenosine; 23. 12.52 >175 24. Adenosine derivatives according to any one of the preceding claims, which are compounds which are only slightly active or inactive at the A3 receptor. 24. 51.70 >134 25. The adenosine derivative according to any one of claims 1-24. - 62 chairs for medical use. 25. 32 - Patent claims 26. Pharmaceutical compositions comprising, in addition to a pharmacologically acceptable carrier and/or binder, one of the adenosine derivatives according to any one of claims 1-24. 27. Use of adenosine derivatives according to any one of claims 1-24 for the preparation of pharmaceutical compositions suitable for the treatment of patients who are in a condition where a reduction in plasma free fatty acid content or heart rate is beneficial, or who suffer from heart disease with local anemia, peripheral vascular disease, pain, stroke, central nervous system disorder or sleep apnea. 28. A process for the preparation of adenosine derivatives according to claim 1, characterized in that a compound of general formula (II) - in general formula (II) L represents a leaving group, P ¹ and P ² represent a hydrogen atom or a suitable protecting group, and R ¹ , R ² and R ³ have the meanings given in claim 1 - is reacted under basic conditions with a compound of general formula R ¹ NH ₂ or a salt thereof. On behalf of GLAXO GROUP LIMITED, the authorized representative: